Depressive symptoms, major depressive disorder (MDD), and cognitive impairment are among the most frequent behavioral problems reported in patients with ESRD receiving maintenance hemodialysis (HD). ESRD/HD patients have marked elevation in plasma inflammatory cytokines, diminished total tryptophan (TRP), and increased levels of free TRP and the TRP catabolites kynurenine (KYN) and quinolinic acid. Increased inflammatory cytokines, decreased TRP, and increased KYN and quinolinic acid are associated with depressive symptoms, MDD, and cognitive dysfunction in humans and work in laboratory animals confirms these associations. The few published studies of antidepressant treatment of MDD in ESRD/HD patients have mostly used the selective serotonin reuptake inhibitor (SSRI) fluoxetine and there is some evidence of efficacy. Bupropion is an antidepressant that does not affect serotonin bur rather blocks the reuptake of norepinephrine and dopamine. Along with its effectiveness in MDD, bupropion also has been found to be effective in treating attention deficit disorder and in improving cognitive and fatigue in MDD patients. Bupropion has also been found to reduce TNF-a in laboratory animals and humans and has been shown to reduce inflammation and improve mood in patients with atopic dermatitis. Therefore, bupropion has the potential to be exceptionally therapeutic in ESRD/HD. However, no study has examined the effects of bupropion on inflammation, depression, fatigue, and cognitive function in ESRD/HD patients. In order to establish the feasibility of a future definitive trial, the current study will randomly asign 40 ESRD/HD patients with MDD to treatment with either fluoxetine or bupropion SR for 12 weeks. Treatment with both fluoxetine and bupropion will be monitored by a psychiatrist psychopharmacologist and dosed to the highest tolerated dose in a flexible dose design. The study will determine the treatment 12 week response and remission rates for MDD with bupropion and fluoxetine, assess their relative tolerability and safety, and longitudinally contras their effects on measures of cognitive function, fatigue, inflammation, and TRP and TRP catabolites. It is hypothesized that both drugs will significantly reduce MDD symptoms from baseline, and be tolerable and safe, but bupropion will be associated with greater reduction in inflammation, cognitive impairment, and fatigue compared with fluoxetine.